Recent epidemiological studies show an association between mid-life obesity, type 2 diabetes mellitus (T2DM), and the development of Alzheimers Disease (AD). Altered processing of Amyloid Precursor Protein (APP) leads to increased neuronal production of pathologic amyloid-b (Ab) fragments, which is a major component of AD pathology. Dysregulated APP processing is associated with insulin resistance, hyperinsulinemia, dyslipidemia, and inflammation, states which typify obesity and T2DM. Adipose tissue is a major site of altered metabolism in obesity and T2DM. It becomes chronically inflamed in obesity contributing in part to altered metabolic function of adipose tissue in T2DM. We recently reported APP is expressed in human adipose tissue cells, upregulated with obesity and T2DM, and correlated to insulin resistance and inflammatory markers. We also found elevated plasma Ab levels are correlated with adipocyte APP expression and measures of insulin resistance. In light of these data, we hypothesize that alteration of adipose tissue APP and Ab in obesity and T2DM is a putative mechanism linking insulin resistant states and AD. Our approach to this hypothesis focuses on whether changes in adipocytes and preadipocytes related to insulin resistant states alter the regulation and processing of adipose APP and will be tested in the following aims: Specific Aim 1: We will test whether adipose tissue cells produce significant amounts of Ab, if this production is a determinant of circulating Ab levels, and if this process is altered by obesity, insulin resistance, and T2DM. Specific Aim 2: We will test whether insulin, glucose, and / or pro-inflammatory factors directly regulate expression of APP or its processing enzymes in adipose tissue cells. Specific Aim 3: To determine whether Ab affects glucose uptake in adipose tissue cells through alterations of insulin receptor signaling and pro-inflammatory pathways. Each of these aims will generate independent and novel data contributing to understanding the role of adipose APP and Ab in insulin resistant states and may suggest new therapeutic targets or preventive strategies for therapy of AD and T2DM. Additionally this project constitutes a rigorous clinical research training program for the applicant with integrated basic and clinical studies and well matched didactics. PUBLIC HEALTH RELEVANCE: Recent epidemiological studies show an association between insulin resistant states such as obesity and type 2 diabetes mellitus and the development of Alzheimer's Disease, a sobering observation as obesity and diabetes are global epidemics. Cell biology studies strongly support the idea that insulin resistance induces cellular changes promoting Alzheimer's Disease;our clinical research group found Amyloid Precursor Protein, a major component of the pathology of Alzheimer's Disease, is expressed in adipose tissue, upregulated with obesity, and correlated with measures of insulin resistance and systemic inflammation. The studies in this application focus on understanding the regulation of adipose tissue Amyloid Precursor Protein in obesity and type 2 diabetes mellitus as a potential molecular mechanism linking insulin resistant states with developing Alzheimer's disease later in life.